Field of the Invention
The present invention relates to a composition for inducing senescence in tumor cells comprising an inhibitor against a 3′-phosphoadenosine 5′-phosphosulfate synthase 2 (PAPSS2) gene or protein encoded by the gene and a method for inducing senescence in tumor cells using the same.
Description of Related Art
Premature senescence, also known as stress-induced premature senescence, in tumor cells means senescence caused in tumor cells by various stimuli. In contrast to normal cells that undergo senescence after a particular number of cell division, tumor cells divide indefinitely due to changes in characteristics of replicative senescence during tumorigenesis, and it has long been known that tumor cells may not undergo cellular senescence. In recent years, however, various stimuli have been known to rapidly induce senescence in tumor cells, which is called stress-induced premature senescence (Sugrue et al., Proc. Natl. Acad. Sci. USA, 94:9648-9653, 1997; Mason et al., Oncogene, 23; 9238-9246, 2004). It has been reported that stress sources capable of inducing senescence in tumor cells are genotoxic chemicals (e.g., etoposide, cyclophosphamide, etc.), radiation, and UV light (Hemann and Narita, Genes & Dev., 21:1-5, 2007; Chang et al., Proc. Natl. Acad. Sci. USA, 99:389-394, 2002).
Suppression of tumor cell proliferation by inducing senescence in tumor cells through stress-induced premature senescence has recently been suggested as an effective mechanism for cancer therapy (Roninson et al., Drug Resist Updates, 4:303-313, 2001; Campisi, Science, 309:886-887, 2005), and studies on the mechanism of cellular senescence contributed to an improvement in the efficiency of cancer therapy (Narita and Lowe, Nature Medicine, 11:920-922, 2005). Moreover, a histological analysis of cancer patients with inhibited malignant progression of tumor reported that senescence was effectively induced in tumor cells (Collado et al., Nature, 436:642, 2005). In addition, the tumor suppressor protein p53 was reported to be implicated in the removal of tumor tissues through cellular senescence, as proven in an animal test (Xue et al., Nature, 445:656-660, 2007). This indicates that cellular senescence can be effectively applied to cancer therapy. In practice, the activation of the senescence mechanism in tumor cells makes it possible to treat cancer with lower doses of anticancer agents or radiation than does the activation of cell death mechanisms, thus improving the side effects associated with conventional cancer therapy and overcoming the resistance to cancer therapy of cancer cells which acquire the resistance to the cell death (Rebbaa, Cancer Lett, 219:1-13, 2005).
Meanwhile, 3′-phosphoadenosine 5′-phosphosulfate synthase 2 (PAPSS2) is a gene with National Center for Biotechnology Information (NCBI) Access No. NM_004670 (SEQ ID NO: 1) or NM_001015880 (SEQ ID NO: 2) and has not been known to be associated with premature senescence in tumor cells in the prior art.